Although 50% to 60% of women are said to experience some degree of pain associated with menstruation, intense menstrual pain requiring remaining in bed or recuperation and some form of medical accommodations is referred to as dysmenorrhea (Non-Patent Document 1). Dysmenorrhea is a syndrome extending from just before the start of menstruation through menstruation that mainly manifests itself with the primary complaints of lower abdominal pain and lower back pain, and is a gynecological disease that may be associated with various associated symptoms (including headache, menorrhagia and malaise).
Dysmenorrhea is a disease that is classified as N94 in the International Classifications of Disease ICD10 issued by the World Health Organization (WHO), and can further be classified into two types. These two types consist of functional (primary) dysmenorrhea (N94.4 in ICD10) and organic (secondary) dysmenorrhea (N94.5 in ICD10) (Non-Patent Document 2).
Functional (primary) dysmenorrhea is not associated with an organic disease in the pelvis, and 90% or more of dysmenorrhea is functional (primary) dysmenorrhea. With respect to the mechanism of onset of functional (primary) dysmenorrhea, although various theories have been advocated regarding the cause thereof, such as hypercontraction of uterine muscle, uterine ischemia, overproduction of prostaglandin F2α, hormone imbalance, poor circulation or psychological factors, the cause has yet to be fully determined and has yet to be identified (Non-Patent Document 1). On the other hand, although organic (secondary) dysmenorrhea is a disease that occurs as one of associated symptoms in the case a well-defined disease is present in the pelvis, such as pelvic congestion syndrome, intrapelvic infection, intrapelvic inflammatory disease, cervical stenosis, uterine myoma, endometrioma, uterine adenomyosis or positional and morphological anomalies of the uterus, it does not necessary occur due to the presence of these organic diseases, and the cause as to why dysmenorrhea occurs in these cases is not fully understood.
Since the lower abdominal pain and lower back pain during the onset of dysmenorrhea is extremely intense, many patients make accommodations by taking an analgesic for the purpose of temporary relief of that pain. Although examples of analgesics primarily include non-steroid anti-inflammatory drugs (NSAID) such as voltaren, ibuprofen or naproxen having cyclooxygenase inhibitory action, none of these have an action that specifically cures dysmenorrhea, but rather merely demonstrate effects in the form of symptomatic therapy that serves to temporarily alleviate pain associated with the disease (Non-Patent Documents 3, 4 and 5). Consequently, there are many cases that do not experience improvement in the level of pain or exacerbation due to progression of the disease state despite having taken such medication for many years. Moreover, analgesics have also been reported to have problems with adverse side effects, such as the occurrence of gastrointestinal disorders or renal disorders, due to long-term use. In the case of voltaren tablets, for example, adverse side effects have been observed to occur at a frequency of 10.85% according to the findings of a pre-approval study, and although these adverse side effects consist mainly of gastrointestinal symptoms such as stomachache, gastric discomfort or abdominal pain (9.43%), other adverse side effects include generalized systemic symptoms such as edema (0.95%) and skin symptoms such as itching and rash (1.56%) (Non-Patent Document 3). In this manner, despite these analgesics that are only taken when needed and do not demonstrate any therapeutic effects, as a result of being associated with numerous adverse side effects, there is a strong desire among patients and clinicians for the development of a therapeutic agent having few adverse side effects.
With respect to the treatment of dysmenorrhea, since the mechanism of occurrence is not fully understood for both functional and organic dysmenorrhea, an effective therapeutic agent has yet to be found. Consequently, in the current clinical setting, treatment is provided by either interrupting or reducing menstruation in serious cases since symptoms of dysmenorrhea always occur in association with menstruation. More specifically, treatment consists of administration of gonadotropins that inhibit the menstrual cycle, hormone preparations that inhibit the production and secretion of sex hormones, decrease ovarian function and induce endometrial atrophy, or low-dose oral contraceptives (pill). Since menstruation is interrupted or menstrual bleeding is reduced as a result of taking these drugs, pain associated with menstruation is considerably improved.
However, since hormone preparations and low-dose oral contraceptives do not treat the focus of dysmenorrhea, intense pain during menstruation frequently recurs when they are no longer taken and anovular menstruation resumes. Moreover, the presence of numerous adverse side effects is also a problem with respect to hormone preparations and low-dose oral contraceptives as well. For example, with respect to Lunabell tablets (tablets having the same ingredients and formulation as Ortho M-21 tablets that have been used as an oral contraceptive), adverse side effects have been reported to occur at a high rate of 87.9%. Primary examples of adverse side effects include abnormal genital bleeding (59.1%), nausea (26.3%), headache (16.2%), oligomenorrhea (14.6%), upper abdominal pain (8.6%), breast discomfort (8.1%) and menorrhagia (7.1%), while thrombosis and anaphylactic symptoms have also been reported as serious adverse side effects (Non-Patent Document 6). In addition, low-dose oral contraceptives have also been reported to increase the risk of the onset or exacerbation of estrogen-dependent malignant tumors
(Non-Patent Document 6). Moreover, due to their inhibitory action on ovulation, they are unsuitable for use by women desiring to bear children since it is not possible to become pregnant while continuing to take these drugs (Non-Patent Documents 6 and 7).
Tranilast is a drug that has been conventionally used for the treatment and/or prevention of mainly bronchial asthma and allergic rhinitis based on its action of inhibiting the release of chemical mediators. In addition, in addition to its inhibitory action on the release of chemical mediators, tranilast also has an action that inhibits collagen synthesis, and is known to have therapeutic effects against diseases involving excessive proliferation of vascular endothelial cells such as restenosis following PTCA, cardiac hypertrophy, atherosclerosis, angiogenesis inhibition, coronary hypertrophy following heart transplant, hypertensive arteriolopathy and heart failure (see Patent Documents 1 to 8). However, tranilast, derivatives thereof or salts thereof are not known to be effective as a prophylactic and/or therapeutic agent for dysmenorrhea and/or associated symptoms thereof, and there have also been no findings suggesting such.
Patent Document 1: Japanese Patent Laid-open Publication No. H5-163222
Patent Document 2: Japanese Patent Laid-open Publication No. H6-135829
Patent Document 3: Japanese Patent Laid-open Publication No. H7-277966
Patent Document 4: Japanese Patent Laid-open Publication No. H9-227371
Patent Document 5: WO 97/29744
Patent Document 6: WO 01/05394
Patent Document 7: WO 01/13911
Patent Document 8: WO 01/13952
Non-Patent Document 1: Modern Physician, Vol. 29, No. 3, p. 399, 2009
Non-Patent Document 2: International Statistical Classification of Diseases and Related Health Problems, 10th Revision Version for 2007, Chapter XIV: Diseases of the Genitourinary System
Non-Patent Document 3: Voltaren Tablets, Interview Form, Revised June 2005 Edition (Revised 9th Edition), p. 11
Non-Patent Document 4: Ibuprofen Tablets/Ibuprofen Powder, Interview Form, Revised January 2010 Edition (13th Edition)
Non-Patent Document 5: Naproxen Tablets/Naproxen Capsules, Interview Form, Revised October 2009 Edition (11th Edition)
Non-Patent Document 6: Lunabell, Interview Form, Revised January 2010 Edition (New Form 4th Edition), p. 30, 31, 9
Non-Patent Document 7: Nuttall I.D., et al., Contraception, 1982; 25: 463-469